Spinal cord injury involves damage to nerve roots or myelinated fibre tracts that carry signals to and from the brain.
The consequences of a spinal cord injury may vary depending on the type, level, and severity of injury, but can be classified into two general categories: complete injury and incomplete injury.
In a complete injury, function below the “neurological” level is lost. Absence of motor and sensory function below a specific spinal level is considered a “complete injury”. Recent evidence suggests that less than 5% of people with “complete” spinal cord injuries recover locomotion.
In an incomplete injury, some sensation and/or movement below the level of the injury is retained. For example, when the ability to contract the anal sphincter voluntarily or to feel peri-anal pinprick or touch is retained, the injury is considered to be “incomplete”.
In addition to loss of sensation and motor function below the level of injury, individuals with spinal cord injuries will also often experience other complications (e.g. dysfunction of the bowel and bladder; sexual dysfunction; loss of breathing; inability or reduced ability to regulate heart rate, blood pressure, sweating and hence body temperature; spasticity; neuropathic pain; autonomic dysreflexia; atrophy of muscle; Superior Mesenteric Artery Syndrome; osteoporosis and bone degeneration; and gallbladder and renal stones).
Current treatment for spinal cord injuries involves the short-term use of anti-inflammatory drugs. However, this may not reduce the paralysing effects of injury or promote re-growth of functional nerve fibres. There is a need for new and improved methods of regenerating neuronal tissue, in particular, reinnervation or remyelination, in such situations.
It is known that certain neurotrophic factors may be used to promote neurite outgrowth in vitro (Sayer F. T., et al., Experimental Neurology, (2002) 175 282-296) however, neurite outgrowth is not a marker for regeneration, but is rather a marker for differentiation. With reference to Tanaka et al., Nature Reviews Neuroscience, 10, 713-723 (2009), the term regeneration requires re-acquiring neuronal function; this obviously is not possible to show in vitro, e.g. in the neurite outgrowth assays. Following spinal cord injury, local expression of various neurotrophic factors (including brain-derived neurotrophic factor, BDNF) decreases, and it has been shown that treatment with neurotrophins promotes regeneration.
Exogenous administration of BDNF has also been shown to promote neural cell survival, alleviate neuronal atrophy, facilitate axonal regeneration, prevent apoptosis, enhance differentiation of neuronal stem cells to neurons followed by improvement of motor functions, and induce glial cell proliferation, axonal outgrowth and myelination (Nakajima H., et al., SPINE, 35(5), 497-504 (2010).
Activation of tropomyosin-related kinase (Trk) receptors (e.g. by BDNF which acts through the TrkB receptor) has been shown to promote neuronal cell survival, differentiation and synaptic function (Massa S. M., et al., J. Clin. Invest., 120, 1774-1785 (2010)).
Certain small molecules have been shown to be capable of mimicking BDNF by activating TrkB signalling (Massa S. M., supra). However these small molecules were not shown to be agonists of the AT2 receptor.
The endogenous hormone AngII is a linear octapeptide (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8), and is the active component of the renin-angiotensin system (RAS). It is produced by the sequential processing of the pro-hormone angiotensinogen by renin and angiotensin converting enzyme (ACE).
The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, body fluid and electrolyte homeostasis. AngII exerts these physiological actions in many organs including the kidneys, the adrenal glands, the heart, blood vessels, the brain, the gastrointestinal tract and the reproductive organs (de Gasparo et al, Pharmacol. Rev. (2000) 52, 415-472).
Two main classes of AngII receptors have been identified, and designated as the type 1 receptor (hereinafter the AT1 receptor) and the AT2 receptor. The AT1 receptor is expressed in most organs, and is believed to be responsible for the majority of the biological effects of AngII. The AT2 receptor is more prevalent than the AT1 receptor in fetal tissues, the adult ovaries, the adrenal medulla and the pancreas. An equal distribution is reported in the brain and uterus (Ardaillou, J. Am. Soc. Nephrol., 10, S30-39 (1999)).
Several studies in adult individuals appear to demonstrate that, in the modulation of the response following AngII stimulation, activation of the AT2 receptor has opposing effects to those mediated by the AT1 receptor.
The AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (see de Gasparo et al, supra). Further, it seems to play a role in blood pressure control. For example, it has been shown in transgenic mice lacking AT2 receptors that their blood pressure was elevated. Furthermore, it has been concluded that the AT2 receptor is involved in exploratory behaviour, pain sensitivity and thermoregulation.
The expression of AT2 receptors has also been shown to occur upon tissue injury in the nervous system after central nervous system lesion (Lucius et al., J. Exp. Med., 188(4), 661-670 (1998).
The expected pharmacological effects of agonism of the AT2 receptor are described generally in de Gasparo et al, supra. It is not mentioned that agonism of the AT2 receptor may be used to treat spinal chord injury.
More recently, AT2 receptor agonists have been shown to be of potential utility in the treatment and/or prophylaxis of disorders of the alimentary tract, such as dyspepsia and irritable bowel syndrome, as well as multiple organ failure (see international patent application WO 99/43339).
Studies have shown that stimulation of the AT2 receptor with AngII promotes axonal regeneration in postnatal retinal explants and dorsal root ganglia in vitro as well as after optic nerve crush in vivo (Lucius et al., supra.). Although AngII is non-selective (i.e. it does not selectively bind to one or more angiotensin receptors in preference to the others) this study showed that it is the binding of AngII to the AT2 receptor that is important in the promotion of axonal regeneration in the model studied.
Studies have also shown that stimulation of the AT2 receptor with AngII promotes neuronal regeneration and functional recovery in rats following damage to their sciatic nerve in vivo (Reinecke K., et al., FASEB J. 2003 17: 2094-2096).
AT2 receptor agonists have also been described in the prior art, for instance in international patent application WO 2002/096883. However, the use of those compounds in the treatment of spinal cord injury is not mentioned. Further, there is no indication that the compounds are capable of mimicking BDNF and activating TrkB signalling in vivo.
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.